PROJECT SUMMARY ABSTRACT The kidney is unique among the body organs in that it responds to early diabetes by growing large and increasing its function and oxygen consumption (QO2). We are drawn to understand this physiology because growth, hyperfunction, and low cortical PO2 in the early diabetic kidney predict subsequent damage and decline. For the past 15 years, we have characterized glomerular and tubular function in the early diabetic kidney with particular emphasis on how glomerular filtration and proximal reabsorption affect each other. This application is focused on the renal effects of dietary salt and of common drugs that are already in the armamentarium of diabetes care. These drugs include inhibitors of the Na-glucose cotransporter SGLT2 and agonists of the glucagon-like peptide 1 receptor (GLP-1R). SGLT2 inhibitors and GLP-1R agonists are being administered to millions of diabetic patients, and lowering of the dietary salt would apply to millions more if public health recommendations were successfully implemented. Each of these maneuvers has off-target effects on glomerular and tubular function, the nuances of which we intend to investigate. The goal is to facilitate the acquisition of medical knowledge by providing a basis in physiology for developing hypotheses that are worth bringing to clinical trials for renal protection and for providing a scientific explanation of the outcome of such trials that are already in progress. The experimental work is divided into 3 Specific Aims. Each aim addresses the impact of dietary salt, SGLT2 blockade, and GLP-1R activation on a particular aspect of kidney physiology. The three aspects of kidney physiology are 1) proximal tubular growth and transport, 2) renal hemodynamics, and 3) renal metabolism. A network assembled from cause-effect relations among transport, hemodynamic, and metabolic variables provides insight to the organic physiology that could not be determined by studying transport, hemodynamics, and metabolism in isolation.